Assessment of pituitary function post pituitary surgery Rola Zamel, R5

Outline - Cases - Our current approach - Preoperative evaluation - Postoperative evaluation - Conclusion

Case 1 Mr.AB 45 YOM Presents with symptoms consistent with VF defect MRI: pituitary tumor 1.5 cm Hormone evaluation Normal

Case 2 Mr.CD 45 YOM Presents with symptoms consistent with VF defect MRI: pituitary tumor 3.0 cm Preoperative hormone evaluation IGF-1 low LH/ FSH/ S.testosterone low TSH 2.5 FT4 9 FT3 2 AM cortisol 50 ACTH low PRL 35

Protocol for managing patients after pituitary surgery Pre-operative: Solucortef mg on call to the OR (Some like to give Decadron 4mg IV as well – check with consultant) Post-operative: Solucortef mg IV q6-8h - decrease by 25-50% each day when over major stress until down to 30 mg per day - switch to equivalent dose of oral hydrocortisone and if stable gradually decrease to 20 mg per day - daily serum electrolytes and osmolality and urine osmolality - I&O hourly- call if>200/hr for 3 consecutive hours or >300/hr for 2 consecutive hours or >400/hr for 1 hour - if output exceeds one of above calculate total I&O and if output exceeds intake order serum electrolytes and osmolality and consider giving ddAVP intranasally or IV - if serum Na >150 or osmoality >300 and urine output >200 give ddAVP On discharge: Give patient OHIP lab order form from Endocrinologist responsible for continuing care for: - electrolytes q 1 (if requiring ddAVP) to 4 weeks (if no ddAVP) - serum free T4 and estradiol/testosterone in two, six and ten weeks - serum cortisol monthly when down to hydrocortisone 20mg daily Instructions given to patients on discharge

Current Practice here: Patient receives stress dosing peri-operatively Hydrocortisone tapered to 20 mg OD (AM) only 8 AM cortisol level (48 hrs after last HC dose): – –cortisol < 100 → pit-adrenal insufficiency – –Cortisol > 500 (550) → sufficient function – –Cortisol : unsure; need stimulation test Stimulation tests can be: – –Insulin tolerance test – –ACTH stimulation test – –(CRH test)

Preoperative assessment of pituitary function A minimum set of pre-operative endocrine tests should include: 1- Electrolytes 2- IGF-1 3- LH/FSH, Estradiol / testosterone 4- TSH, FT3,FT4 5- AM (8-9) Cortisol 6- Prolactin

Interpretation of serum prolactin levels A- high PRL 1- R/O 2 nd causes of high prolactin Eg. Pregnancy, PRL- elevating drugs, primary hypothyroidism, PCOS 2- if PRL >200 mcg/l is diagnostic of macroprolactinoma 3- <80 mcg/l in macroprolactinoma indicates disconnection

4- R/O the hook effect and macroprolactin B- Low PRL Acquired PRL deficiency in a patient not taking PRL lowering medication is associated with severe hypopituitarism and reduced IGF-1 levels Acquired PRL deficiency in a patient not taking PRL lowering medication is associated with severe hypopituitarism and reduced IGF-1 levels

HPAPrecaution: 1- Patient on glucocorticoids 2- Patients on E2, need to hold E2 6 weeks prior to the test

Several tests are available to help predict whether the HPA is able to respond to a significant stress; 1- Basal cortisol - - Should be measured 8-9 AM since HPA activity is maximal at this time - - If am cortisol <100nmol/l replacement should start - - If >450 nmol/l adrenal insufficiency is unlikely

100 < am cortisol< 450, then a provocative test: - ITT - Glucagon stimulation test - ACTH stimulation test ( iv 250 mcg) - CRH test ( not recommended)

GH IGF-1 axis - - IGF1 - - GH provocative tests: the gold standard is ITT Arginine-GHRH test

Hypothalamus – pituitary – thyroid axis - TSH, Free T4 - NTI can cause a pattern of low T4, N/ ↓/↑ TSH Hypothalamus-pituitary-gonadal function - Gonadotropins/sex steroids ( E2 and AM testosterone)

DI - Uncommon preoperatively in setting of pituitary adenoma - Occurs commonly in Craniopharyngioma or other hypothalamic pathology - S.Na, Osmol, U.Osmol

Postoperative assessment of the patient after transsphenoidal pituitary surgery Early post-operative period ( 1 st few weeks post OR): 1-Neurosurgical monitoring for: - disturbances in vision or neurological function - CSF leak (drainage of clear fluid from the nose, especially on bending over) - meningitis: periop AB’s was shown to reduce incidence - Nasal packs are removed 12–24 h after surgery - Nasal packs are removed 12–24 h after surgery

2-Monitoring for water imbalances DI Can occur at any time, peaks in the 1 st 48h - Monitoring of thirst (craving for cold liquids), volume status - Monitoring of thirst (craving for cold liquids), volume status - Ins/outs - Ins/outs - specific gravities - specific gravities - daily serum electrolyte measurements - daily serum electrolyte measurements

Diagnostic criteria: Urine specific gravity 250 cc/hr for 2-3 hours Indications for desmopressin therapy: Patient unable to maintain adequate oral fluid intake, urine output >> fluid intake, hypernatremia

SIADH - Peaks in the 7 th postoperative day - Home monitoring of fluid intake and urine output after discharge in patients with DI postoperatively - Measure serum sodium emergently if symptoms of hyponatremia (headache, nausea and vomiting, mental status changes or seizure)

- Measurement of serum sodium one week after surgery in all patients (isolated hypoNa after TS was reported) - Fluid restriction (~ 800cc/d depending on severity of hyponatremia)

3-What about Ant pituitary deficiency? The development of new pituitary hormone deficiencies after TS is uncommon when performed by an experienced pituitary surgeon The development of new pituitary hormone deficiencies after TS is uncommon when performed by an experienced pituitary surgeon

Predictors of hypopituitarism post TS 1-When the surgical procedure is more extensive, hemorrhage or necrosis within the tumor are seen 2- DI:the likelihood of postoperative AI was found to be increased four-fold in patients who had post-operative DI 3-Type of pituitary lesion: non-pituitary lesions such as craniopharyngiomas are more likely to be accompanied by hypopituitarism or DI

3-Pituitary–adrenal axis assessment No RCTs No RCTs Various strategies exist for ensuring the integrity of this axis

1- IV HC 100 mg at time of surgery, this dose is tapered quickly over two to three days 2- dexamethasone at doses of 2 mg at the time of surgery and 1 mg bid on postoperative day 1 Postoperative assessment of the patient after transsphenoidal pituitary surgery (Ausiello J et al. Pituitary 2008) 2- dexamethasone at doses of 2 mg at the time of surgery and 1 mg bid on postoperative day 1 Postoperative assessment of the patient after transsphenoidal pituitary surgery (Ausiello J et al. Pituitary 2008)

3- Some recommend administering these to patients with preoperative hypopituitarism but withholding them in those with normal preoperative pituitary–adrenal function [peak cortisol >496.8 nmol/l (18 μg/dl) post 250 μg cosyntropin stimulation] in whom only selective adenomectomy is planned Inder WJ, Hunt PJ (2002) Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab

Inder WJ, Hunt PJ (2002) Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab

Prior to hospital discharge after TS each patient needs an assessment of pituitary– adrenal axis integrity The 250 μg CST: is not the test of choice for early post-operative assessment of pituitary-adrenal function because of its inability to detect recent onset secondary AI ITT: not be clinically appropriate within the first few days after surgery

AM postoperative cortisol: the accuracy of this test for the prediction of secondary AI has been investigated

How early after surgery one may safely assess patients for adequacy of adrenal function? Immediate postoperative cortisol levels accurately predict postoperative hypothalamic–pituitary–adrenal axis function after transsphenoidal surgery for pituitary tumors. Pituitary March 26,2010 Goal to examine the ability of a normal preoperative ACTH stimulation test to predict an adequate postoperative stress response and normal HPA axis function. Results of preop CST was compared to immediate post op DOS S.cortisol and late post op CST

-A prospective study -100 patients ( pituitary adenoma (n = 99) or a Rathke’s cleft cyst (n = 1) who underwent transsphenoidal surgery by a single neurosurgeon between October 2006 and March 2009) Cleveland Clinic

- Exclusion criteria: 1- Patients undergoing surgery for Cushing’s disease 1- Patients undergoing surgery for Cushing’s disease 2- patients who chronically received daily corticosteroids prior to surgery 2- patients who chronically received daily corticosteroids prior to surgery 3- patients who did not have a preoperative ACTH stimulation test or who failed to follow up appropriately for postoperative testing 3- patients who did not have a preoperative ACTH stimulation test or who failed to follow up appropriately for postoperative testing 4- patients who failed preoperative ACTH stimulation test 4- patients who failed preoperative ACTH stimulation test

Method - All patients were tested preoperatively with a modified low-dose (25 μg) CST to evaluate HPA axis function. - All patients were tested preoperatively with a modified low-dose (25 μg) CST to evaluate HPA axis function. - Serum total cortisol levels were assayed at 0, 30 and 60 min post injection. An adequate and sufficient response was defined as an absolute cortisol level of ≥18 μg/dL (496.8 nmol/l) at either t 30 or t Serum total cortisol levels were assayed at 0, 30 and 60 min post injection. An adequate and sufficient response was defined as an absolute cortisol level of ≥18 μg/dL (496.8 nmol/l) at either t 30 or t 60.

- Patients with normal pre-operative HPA axis function did not receive glucocorticoid coverage during pituitary surgery - All patients had: * S.cortisol immediately post op, * S.cortisol immediately post op, * modified low-dose CST at 4–6 weeks postoperatively * modified low-dose CST at 4–6 weeks postoperatively * F/U at 3 months, one year, and then at one year intervals thereafter. Laboratory assays of HPA axis function were performed at these visits if clinical symptoms suggestive of hypocortisolemia were present, with a mean follow-up of 22 months * F/U at 3 months, one year, and then at one year intervals thereafter. Laboratory assays of HPA axis function were performed at these visits if clinical symptoms suggestive of hypocortisolemia were present, with a mean follow-up of 22 months

Results - In patients in whom adequate pre-operative adrenal function is demonstrated, an immediate postoperative cortisol level ≥15 μg/dL has a similar or greater ability to predict normal postoperative HPA axis function as does determination of cortisol levels on POD1 or later

In most centers, therefore, cortisol levels are measured the morning of the 2nd or 3rd postoperative day, 24 h after the last dose of peri-operative hydrocortisone coverage 1- AM cortisol levels >17 μg/dl (460 nmol/L) do not require replacement on discharge 2- level <10 ug/dl ( 270nmol/L) require 3- AM cortisol levels between 10 and 17 debatable, some argue that these patients should receive further therapy, some Rx if symptoms of AI, some Rx if DI or complicated surgery

- In most centers; morning cortisol levels are reassessed 1 week postoperatively, 24 h after the most recent dose of hydrocortisone ………………………………………………….. Despite the many studies on this question, there is still disagreement regarding the morning cortisol level that best predicts normal HPA axis function in stressed and unstressed situations so some centers treat all postoperative patients with oral glucocorticoid therapy on discharge and continue this until at least the first postoperative visit

Other anterior pituitary hormone assessments - One report suggests measuring FT4 one week postoperatively in patients with: 1- other abnormalities of pituitary function 2- unknown preoperative thyroid function 1- other abnormalities of pituitary function 2- unknown preoperative thyroid function 3- pituitary apoplexy 3- pituitary apoplexy……………………………………………………………………

In patients with prolactinomas, who may undergo TS because they are resistant to or intolerant of dopamine agonists, early measurement of prolactin levels can be undertaken as low levels may portend a better surgical outcome ………………………………………………………… Assessment of growth hormone and gonadotropins is reserved for a later postoperative visit Assessment of growth hormone and gonadotropins is reserved for a later postoperative visit

Late postoperative phase - new hypopituitarism is very rare after TS in patients with intact pituitary function preoperatively. - In general, most cases of new hypopituitarism are detected very early post-operatively and almost always within the first 3 months

- In one retrospective study of 71 patients 32 developed AI but none developed AI after 3 months post OR. Adrenocortical insufficiency after pituitary surgery: an audit of the reliability of the conventional short synacthen test Clin Endocrinol (Oxf) Nov;63(5):

Assessment of the pituitary–adrenal axis 1-Measure morning cortisol at first postoperative visit 24- hrs after glucocorticoid dose if on therapy) 2-Assess cortisol level and clinical status * If AM cortisol <100 nmol/L ( 3.7) likely to remain ACTH deficient, but late recovery was documented * If AM cortisol <100 nmol/L ( 3.7) likely to remain ACTH deficient, but late recovery was documented * Some recommend D/C steroid if am.cortisol >10 and no other hypopituitarism, others use >18 * Some recommend D/C steroid if am.cortisol >10 and no other hypopituitarism, others use >18

3-Consider further testing of pituitary-adrenal function: 1- ITT ( the gold standard for assessing HPA) Normal response >500 nm 2- Cosyntropin stimulation test (250 μg) (CST can be used 4 weeks post OR) Normal response >550 nm 3- Glucagon stimulation test The recommended dose is 1 mg IM Adequate response is >500nm 4- CRH test Is not recommended as it is inferior to 8AM s.cortisol for assessing HPA in pituitary disease It doesn’t provided further info in the group with intermediate cortisol level nM

- Optimal timing of the tests to assess HPA is controversial - Some recommend s.cortisol at d 7 and definitive testing 7-14 days and definitive testing 7-14 days then review in clinic at 3-4 weeks then review in clinic at 3-4 weeks - Other approach is to perform definitive test between 4-6 weeks post op

Thyroid axis Thyroid function can be assessed by measuring free thyroxine levels at the first postoperative visit, again some time within the first few months after surgery and on a yearly basis thereafter Thyroid function can be assessed by measuring free thyroxine levels at the first postoperative visit, again some time within the first few months after surgery and on a yearly basis thereafter

Pituitary–gonadal axes - In premenopausal women gonadal function can be assessed based on menstrual history and gonadotropin and estradiol levels if necessary - Male: 1- Assess for symptoms of hypogonadism 2- gonadotropin levels, and a morning total testosterone. A free testosterone may be necessary in patients at risk for abnormal SHBG levels (elderly, obese, thyroid illness or other significant comorbidities)

Growth hormone axis The optimal time postoperatively to assess for and begin GHD therapy is not yet established Method 1- ITT 2- arginine/GHRH test

Radiologic evaluation MRI 3 months post op Then q1yr X 5 yrs Then can lengthen interval if stable

Long term monitoring with assessments of visual, neurological and pituitary function coupled with pituitary imaging is necessary for all patients who have undergone surgery, irrespective of the hormone status of their tumors.

Assessments in patients with hormone secreting pituitary tumors 1- ACTH secreting tumors a- administer stress glucocorticoids and taper to about twice replacement doses postoperatively b- Other approach is to withhold peri-operative and early postoperative glucocorticoids until remission or persistent disease is documented. S.cortisol q6 h and monitor for signs and symptoms of AI If cortisol <55.2 nmol/l (2 μg/dl) and patients have symptoms, remission is achieved and replacement glucocorticoids are begun If cortisol <55.2 nmol/l (2 μg/dl) and patients have symptoms, remission is achieved and replacement glucocorticoids are begun

GH-secreting tumors Preliminary assessment of recovery Can be done by measuring GH level on the 3rd postoperative day. The lower the GH level, the better the evidence for remission

Conclusion Do we need to change our protocol?

References 1-Preoperative assessment for pituitary surgery.Pereira O, Bevan JS.Pituitary. 2008;11(4): Review. Preoperative assessment for pituitary surgery.Preoperative assessment for pituitary surgery. 2-Postoperative assessment of the patient after transsphenoidal pituitary surgery Ausiello et alPituitary. 2008;11(4): Ausiello 3-Immediate postoperative cortisol levels accurately predict postoperative hypothalamic–pituitary–adrenal axis function after transsphenoidal surgery for pituitary tumors. Pituitary March 26, Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management.Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab Jun;87(6): Review. 5-Adrenocortical insufficiency after pituitary surgery: an audit of the reliability of the conventional short synacthen test. Clin Endocrinol (Oxf) Nov;63(5):